Methods of administering anti-fibrotic therapy

ABSTRACT

The present disclosure relates to methods of administering Compound I for treating fibrotic disorders, inflammatory disorders or autoimmune disorders.

BACKGROUND

This is the U.S. National Stage pf PCT/US2017/063549, filed Nov. 29,2017, which claims the benefit under 35 U.S.C. § 119(e) of U.S.Provisional Patent Application Nos. 62/428,163, filed Nov. 30, 2016, and62/432,425, filed Dec. 9, 2016, and the disclosures thereof are herebyincorporated by reference herein.

BACKGROUND Field

The present disclosure relates to methods of administering Compound I.

Description

Compound I is an orally available small molecule having the structure:

Compound I has therapeutic value in several different indications thatdisplay fibrotic pathophysiology, such as idiopathic pulmonary fibrosis(IPF).

Idiopathic pulmonary fibrosis is a disease of unknown etiology thatoccurs mainly in middle-aged and elderly patients, which ischaracterized by progressive fibrosis of the lung, leading to pulmonaryinsufficiency and death. Because fibrosis has long been considered to bea clinically irreversible process, treatments have traditionally beenfocused on managing the symptoms and complications, with little hope ofsignificantly slowing progression of the condition. For many years,mainstay treatments have been typically anti-inflammatory,immunosuppressive, and anti-oxidant agents. The effectiveness of thesetherapies in the treatment of IPF and other fibrotic conditions appearsto be minimal and variable, and their side effects are often poorlytolerated by patients.

New treatment options have only recently become available. Bothpirfenidone and nintedanib have been approved for use in the treatmentof IPF. Current research efforts to develop new anti-fibrotic agents aretargeting multiple mechanisms proposed to be linked to the underlyingmolecular pathogenic processes. This changing landscape has raised hopesand expectations for what might be achievable with new single agents orcombination therapies targeting additional pathways.

SUMMARY

Unexpected food effects have now been identified for Compound Itherapies. Described herein are clinical trials that reveal that theadministration of Compound I with food unexpectedly increases thebioavailability of the drug, indicating a positive food effect. Forexample, the administration of Compound I with either a high fat or alow fat meal improves the C_(max) and AUC of the drug, thereby improvingthe efficacy of the treatment.

Some embodiments of the present disclosure relate to methods ofadministering Compound I to treat a patient suffering from a fibroticdisorder, an inflammatory disorder, or an autoimmune disorder,comprising administering a therapeutically effective amount of CompoundI in combination with food.

Some embodiments of the present disclosure relate to methods ofincreasing drug bioavailability in Compound I therapy to treat a subjectsuffering from a fibrotic disorder, an inflammatory disorder, or anautoimmune disorder, comprising: administering to a subject atherapeutically effective amount of Compound I with food, wherein thebioavailability of Compound I is increased compared to thebioavailability of the same amount of Compound I administered withoutfood.

Some embodiments of the present disclosure relate to methods ofproviding Compound I therapy to a subject, comprising providing atherapeutically effective amount of Compound I to the subject; andadvising the subject not to take a gastric acid reducing agentconcomitantly with Compound I. In some embodiment, the gastric acidreducing agent is a proton pump inhibitor (PPI). Some embodiments of thepresent disclosure relate to methods of providing Compound I therapy toa subject, comprising providing a therapeutically effective amount ofCompound I to the subject; and advising the subject that taking a PPIconcomitantly with Compound I may require dose adjustment of Compound I.Some embodiments of the present disclosure relate to methods ofproviding Compound I therapy to a subject taking a PPI, comprisingproviding a therapeutically effective amount of Compound I to thesubject taking a PPI; wherein the therapeutically effective amount ofCompound I in the subject taking a PPI is greater than thetherapeutically effective amount of Compound I in a subject not taking aPPI.

Some further embodiments of the present disclosure relate to methods forproviding Compound I therapy, comprising administering a therapeuticallyeffective amount of Compound I to a subject having an intra-gastric pHequal to or less than 4.

Some further embodiments of the present disclosure relate to methods ofproviding Compound I therapy to a subject, comprising evaluating therenal function of the subject; and administering a therapeuticallyeffective amount of Compound I to the subject. In some embodiments,evaluating the renal function of the subject comprises determining thesubject's creatinine clearance rate. In some embodiments, the renalfunction of the subject is evaluated prior to administering thetherapeutically effective amount of Compound I to the subject. In someembodiments, the renal function of the subject is evaluated afteradministering the therapeutically effective amount of Compound I to thesubject.

Some further embodiments of the present disclosure relate to methods ofproviding an anti-fibrotic therapy to a subject, comprising evaluatingthe renal function of the subject; advising the subject to not takeCompound I; and providing anti-fibrotic therapy other than Compound I.

Some additional embodiments of the present disclosure relate to kitscomprising a pharmaceutical composition, prescribing information, and acontainer, wherein the pharmaceutical composition comprises atherapeutically effective amount of Compound I.

In any embodiment of the methods or kits described herein, the effectivedaily amount of Compound I is from about 1 mg to about 5000 mg per day,about 5 mg to about 2500 mg per day, or about 10 mg to about 2000 mg perday. In some further embodiments, the amount of Compound I administeredis from about 25 mg to about 1600 mg per day. In some furtherembodiments, the amount of Compound I administered is about 25 mg, about75 mg, about 200 mg, about 275 mg, about 400 mg, about 550 mg, about 575mg, about 800 mg, about 1150 mg, or about 1600 mg per day, or in a rangedefined by any two of the preceding values.

In any embodiment of the methods described herein, the subject treatedis suffering from a fibrotic disorder, in particular idiopathicpulmonary fibrosis (IPF).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates the mean change in serum creatinine from a combinedscreening and pre-dose baseline in the Multiple Ascending Dose (MAD)part of the clinical study described herein.

FIG. 2 illustrates the mean change in creatinine levels from screeninglevel in the MAD part of the clinical study described herein. Analysisvisits were on Day 1 (D1); Day 5 (D5); Day 7 (D7); Day 10 (D10) and atFollow Up (FU).

DETAILED DESCRIPTION

Various embodiments described herein provide methods of increasing thebioavailability of Compound I by administering Compound I with food.Increasing the bioavailability of Compound I has various benefits. Forexample, increased bioavailability can result in more effective dosing.In some embodiments, more effective dosing allows for a lower dosage ofCompound I to be administered to an individual. In some embodiments,administration of Compound I with food can also reduce the frequencyand/or severity of adverse effects associated with Compound I, or otherdrugs.

The section headings used herein are for organizational purposes onlyand are not to be construed as limiting the subject matter described.

As used herein, common abbreviations are defined as follows:

-   -   AE Adverse event    -   Ae₀₋₁₂ amount of drug excreted in the first 12 hours    -   Ae₀₋₂₄ amount of drug excreted in the first 24 hours    -   ANOVA analysis of variance    -   AUC area under the concentration-time curve    -   BID Twice daily    -   CI Confidence interval    -   CLcr Creatinine clearance    -   C_(max) Maximum plasma concentration    -   eGFR Estimated glomerular filtration rate    -   ESRD End stage renal disease    -   fe₀₋₁₂ Percentage of drug excreted in the first 12 hours    -   fe₀₋₂₄ Percentage of drug excreted in the first 24 hours    -   PK Pharmacokinetics    -   PPI Proton pump inhibitor    -   QD Once daily    -   RA_(Auc) accumulation ratio based upon area under the plasma        concentration time curve during the dosing interval    -   SAD Single ascending dose    -   Scr Serum creatinine    -   SD Standard deviation    -   t_(1/2) Apparent plasma terminal elimination half life    -   TEAE Treatment-emergent adverse event    -   T_(last) Time to last measurable concentration

As used herein, the term “with food” is defined to mean, in general, thecondition of having consumed food during the period between from about 1hour prior to the administration of Compound I to about 2 hours afterthe administration of Compound I. In some embodiments, the food is asolid food with sufficient bulk and fat content that it is not rapidlydissolved and absorbed in the stomach. Preferably, the food is a meal,such as breakfast, lunch, or dinner. In some embodiments, the food is atleast about 100 calories, about 200 calories, about 250 calories, about300 calories, about 400 calories, about 500 calories, about 600calories, about 700 calories, about 800 calories, about 900 calories,about 1000 calories, about 1250 calories, about 1500 calories.

As used herein, the term “high fat meal” refers to a meal where fataccounts for about 50% or more of the total calorie-content of the meal.

As used herein, the term “medium fat meal” refers to a meal where fataccounts for about 26-49% of the total calorie-content of the meal.

As used herein, the term “low fat meal” refers to a meal where fataccounts for about 25% or less of the total calorie-content of the meal.

The terms “without food,” “fasted,” or “on an empty stomach” are definedto mean the condition of not having consumed food within the time periodof about 1 hour prior to the administration of Compound I to about 2hours after the administration of Compound I. In some embodiments, foodhas not been consumed for about 10 hours, about 8 hours, about 6 hours,about 4 hours, about 2 hours prior to administration of Compound I.

The term “oral dosage form,” as used herein, has its ordinary meaning asunderstood by those skilled in the art and thus includes, by way ofnon-limiting example, a formulation of a drug or drugs in a formadministrable to a human, including pills, tablets, cores, capsules,caplets, loose powder, solutions, and suspensions.

The term “food effect,” as used herein, refers to a phenomenon that caninfluence the absorption of drugs following administration. A foodeffect can be designated “negative” when absorption is decreased, or“positive” when absorption is increased and manifested as an increase inbioavailability (e.g., as reflected by AUC). Food effects can also referto changes in maximum concentration (C_(max)), or the time to reachmaximum concentration (T_(max)), independently of overall absorption. Asa result, some drugs can preferably be taken in either fasted or fedconditions to achieve an optimum desired effect. As used herein, theterms “with food” and “fed” can be used interchangeably. As used herein,the terms “without food,” “fasted,” and “fasting” can be usedinterchangeably.

The term “renal impairment,” as used herein, refers to impaired renalfunction as defined in the FDA Draft Guidance, Pharmacokinetics inPatients with Impaired Renal Function—Study Design, Data Analysis, andImpact on Dosing and Labeling (Mar. 22, 2010) summarized in thefollowing table.

Classification of Renal Function Based on Estimated GFR (eGFR) orEstimated Creatinine Clearance (CLcr)^(a) eGFR^(c) CLcr^(d) StageDescription^(b) (mL/min/1.73 m²) (mL/min) 1 Control (normal) ≥90 ≥90 GFR2 Mild decrease in 60-89 60-89 GFR 3 Moderate decrease 30-59 30-59 inGFR 4 Severe decrease in 45-29 15-29 GFR 5 End Stage Renal <15 not ondialysis <15 not on dialysis Disease (ESRD) Requiring dialysis Requiringdialysis ^(a)In some situations, collection of 24-hour urine samples formeasurement of creatinine clearance, or measurement of clearance of anexogenous filtration marker, may provide better estimates of GFR thanthe prediction equations. The situations include determination of GFRfor patients in the following scenarios: undergoing kidney replacementtherapy; acute renal failure; extremes of age, body size, or musclemass; conditions of severe malnutrition or obesity; disease of skeletalmuscle; or on a vegetarian diet. ^(b)Stages of renal impairment arebased on K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease(CKD) from the National Kidney Foundation in 2002; GFR: glomerularfiltration rate; ^(c)eGFR: estimate of GFR based on an MDRD equation;^(d)CLcr: estimated creatinine clearance based on the C-G equation.

The terms “pharmacokinetic profile” or “pharmacokinetics,” as usedherein, have their ordinary meaning as understood by those skilled inthe art and thus include, by way of non-limiting example, acharacteristic of the curve that results from plotting concentration(e.g. blood plasma, serum or tissue) of a drug over time, followingadministration of the drug to a subject. A pharmacokinetic profile thusincludes a pharmacokinetic parameter or set of parameters that can beused to characterize the pharmacokinetics of a particular drug or dosageform when administered to a suitable population. In some embodiments,the suitable population may be defined as patients with renalimpairment, patients with hepatic impairment, geriatrics, or pediatrics,etc. Various pharmacokinetic parameters are known to those skilled inthe art, including area under the concentration vs. time curve (AUC),area under the concentration time curve from time zero until lastquantifiable sample time (AUC_(0-t)), area under the concentration timecurve from time zero extrapolated to infinity (AUC_(0- oo) ), area underthe concentration time curve over the steady state dosing interval(AUC_(ss)) or from time zero to twelve hours (AUC₀₋₁₂) for twice-dailydosing, maximum concentration (e.g. blood plasma/serum) afteradministration (C_(max)), minimum concentration (e.g. bloodplasma/serum) after administration (C_(min)), and time to reach maximumconcentration (e.g. blood plasma/serum) after administration (T_(max)).AUC_(last) indicates the area under the blood plasma concentration vs.time curve from the time of administration until the time of the lastquantifiable concentration. Pharmacokinetic parameters may be measuredin various ways known to those skilled in the art, e.g., for single doseor steady-state. Differences in one or more of the pharmacokineticparameters (e.g., C_(max)) may indicate pharmacokinetic distinctnessbetween two formulations or between two methods of administration.

The terms “patient” or “subject” refers to a human patient.

As used herein, the act of “providing” includes supplying, acquiring, oradministering (including self-administering) a composition describedherein.

As used herein, the term “administering” a drug includes an individualobtaining and taking a drug on their own. For example, in someembodiments, an individual obtains a drug from a pharmacy andself-administers the drug in accordance with the methods providedherein.

In any of the embodiments described herein, methods of treatment canalternatively entail use claims, such as Swiss-type use claims. Forexample, a method of treating a fibrotic disorder with a composition canalternatively entail the use of a composition in the manufacture of amedicament for the treatment of a fibrotic disorder, in particular IPF,or the use of a composition for the treatment of a fibrotic disorder, inparticular IPF.

Those skilled in the art will understand that pharmacokinetic parametersmay be determined by comparison to a reference standard using clinicaltrial methods known and accepted by those skilled in the art, e.g., asdescribed in the examples set forth herein. Since the pharmacokineticsof a drug can vary from patient to patient, such clinical trialsgenerally involve multiple patients and appropriate statistical analysesof the resulting data (e.g., ANOVA at 90% confidence). Comparisons ofpharmacokinetic parameters can be on a dose-adjusted basis, asunderstood by those skilled in the art.

Some embodiments of the present disclosure relate to methods ofadministering Compound I to treat a subject suffering from a fibroticdisorder, an inflammatory disorder, or an autoimmune disorder,comprising administering a therapeutically effective amount of CompoundI in combination with food.

The methods disclosed herein include administering Compound I to apatient or subject with food. The Compound I can be administered anytime of day with food. For example, in some embodiments, the food can beconsumed at any time during the period between from about 1 hour priorto the administration of Compound I to about 2 hours after theadministration of Compound I. In some embodiments, the food can beconsumed within the time period of about 1 hour, about 45 minutes, about30 minutes, about 15 minutes, about 10 minutes, or about 5 minutes priorto the administration of Compound I. In some embodiments, the food canbe consumed within the time period of about 5 minutes, about 10 minutes,about 15 minutes, about 30 minutes, about 45 minutes, about 1 hour,about 1.5 hours, or about 2 hours after the administration of CompoundI. In some embodiments, the administration of Compound I to the patientis immediately after the consumption of food (e.g., within about 1minute after food consumption) up to about 1 hour after foodconsumption. In some embodiments, Compound I is administered atsubstantially the same time as the consumption of the food.

In some embodiments, the amount of Compound I administered is from about1 mg to about 5000 mg per day, about 5 mg to about 2500 mg per day, orabout 10 mg to about 2000 mg per day. In some further embodiments, theamount of Compound I administered is from about 25 mg to about 1600 mgper day. In some further embodiments, the amount of Compound Iadministered is about 25 mg, about 75 mg, about 200 mg, about 275 mg,about 400 mg, about 550 mg, about 575 mg, about 800 mg, about 1150 mg,or about 1600 mg per day, or in a range defined by any two of thepreceding values. In one embodiment, Compound I is administered 400 mgper day. In another embodiment, Compound I is administered 550 mg perday. In yet another embodiment, Compound I is administered 800 mg perday.

The dosing may be once or twice or three times daily, with one or moreunits per dose. In some embodiments, the effective daily intake ofCompound I is administered as one, two, three, four, five, six, or moredoses administered separately at appropriate intervals throughout theday. In some embodiments of the methods described herein, Compound I isadministered once daily. In some other embodiments, Compound I isadministered two or more times daily. In one embodiment, Compound I isadministered twice daily. In another embodiment, Compound I isadministered three times daily. In some embodiments, each dose comprisesone, two, three or more unit dosage forms. For example, in someembodiments, one or more units are administered to the subject one ormore times per day. In some embodiments, Compound I is administered asmultiple doses spaced throughout the day and each dose comprises atherapeutically effective amount of Compound I. In some embodiments,Compound I is administered with food once per day.

In some embodiments, Compound I is administered to the subject in a unitdosage form comprising about 25 mg to about 500 mg, or about 50 mg toabout 400 mg, or about 100 mg to about 200 mg Compound I per unit. In anembodiment, Compound I is administered to the subject in a unit dosageform comprising about 25 mg of Compound I per capsule or tablet. Inanother embodiment, Compound I is administered to the subject in a unitdosage form comprising about 200 mg of Compound I per capsule or tablet.As used herein, the term “unit dosage form,” refers to physicallydiscrete units suitable as unitary dosages for human and animalsubjects, each unit containing a predetermined quantity of Compound Icalculated in an amount sufficient to produce the desired effect inassociation with a pharmaceutically acceptable diluent, carrier orvehicle. In some embodiments, the unit dosage form is, for example, apill, capsule, or tablet. In one embodiment, the unit dosage form is atablet.

In some embodiments, the methods include administering a therapeuticallyacceptable amount of Compound I. The term “therapeutically effectiveamount” as used herein, refers to an amount of Compound I sufficient totreat, ameliorate, or prevent the identified disease or condition, or toexhibit a detectable therapeutic effect. The effect may be detected byany means known in the art. In some embodiments, the precise effectiveamount for a subject can depend upon the subject's body weight, size,and health; the nature and extent of the condition; and the therapeuticor combination of therapeutics selected for administration.Therapeutically effective amounts for a given situation may bedetermined by routine experimentation that is within the skill andjudgment of the clinician.

In some embodiments of the methods described herein, the food isselected from a low fat meal, a medium fat meal or a high fat meal. Inone embodiment, the food is a high fat meal.

In some embodiments, the methods comprise avoiding concomitantadministration of a gastric acid-reducing therapeutic. In someembodiments, the gastric acid-reducing therapeutic is a proton pumpinhibitor (PPI), a histamine 2 receptor antagonist (H2RA), and/or anantacid. In some embodiments, the gastric acid-reducing therapeutic is aPPI. In some embodiments, the PPI is selected from omeprazole,lansoprazole, pantoprazole, esomeprazole, rabeprazole, anddexlansoprazole. In some embodiments, the gastric acid-reducingtherapeutic is an H2RA. In some embodiments, the H2RA is selected fromcimetidine, famotidine, nizatidine, and ranitidine. In some embodiments,the gastric acid-reducing therapeutic is an antacid. In someembodiments, the antacid is selected from aluminum hydroxide/carbonate,calcium hydroxide/carbonate, and bismuth subsalicylate. In someembodiments, the methods comprise administering a re-acidificationcompound and Compound I to a patient receiving a gastric acid-reducingagent. In some embodiments, the re-acidification compound is selectedfrom betaine hydrochloride and glutamic acid hydrochloride. In someembodiments, the methods comprise avoiding concomitant administration ofa proton pump inhibitor (PPI), for example, avoiding concomitantadministration of a PPI causing a 24-hour mean intra-gastric pH of equalor over about 6.0, 5.0, 4.0, 3.0, 2.0, or 1.0, or a range defined any ofthe two preceding values. In one embodiment, PPIs causing a 24-hour meanintra-gastric pH of equal or over 4 should be avoided. In anotherembodiment, PPIs causing a 24-hour mean intra-gastric pH of equal orover 3 should be avoided. In some further embodiments, the methodscomprise avoiding administration of a proton pump inhibitor prior to orsubsequent to the administration of Compound I.

Some embodiments of the present disclosure relate to methods ofincreasing drug bioavailability in Compound I therapy to treat a subjectsuffering from a fibrotic disorder, an inflammatory disorder, or anautoimmune disorder, comprising: administering to a subject atherapeutically effective amount of Compound I with food, wherein thebioavailability of Compound I is increased compared to thebioavailability of the same amount of Compound I administered withoutfood.

An increase in bioavailability can be determined using one or moremeasures known to one of skill in the art, such as an increase in AUC orC_(max), which can each independently be an increase that is, is about,is at least, or is at least about, 5%, 10%, 20%, 30%, 40%, 50%, 75%,100%, 125%, 150%, 175%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%,700%, or more, or within a range defined by any two of these values(e.g., 5%-500%, 10%-400%, or 20%-300%), wherein the increase is ascompared to a reference treatment (e.g., a fasted state or a differentfed state). In some embodiments, increasing the bioavailability ofCompound I comprises increasing the maximal plasma concentration(C_(max)) or the extent of absorption (AUC_(0-t) or AUC_(0-∞)) ofCompound I.

In some such embodiments, the increase in bioavailability comprises anincrease in C_(max) of Compound I in the range of about 10% to about400%, about 15% to about 300%, or about 20% to about 250% when CompoundI is taken with food compared to the same amount of Compound I takenduring a fasted condition. In some further embodiments, the increase inC_(max) of Compound I is in the range of about 20% to about 200%, about40% to about 150%, or about 60% to about 125%. In one embodiment, theincrease in C_(max) of Compound I is about 64%. In another embodiment,the increase in C_(max) is about 69%. In yet another embodiment, theincrease in C_(max) is about 126%.

In some such embodiments, the increase in bioavailability comprises anincrease in AUC_(0-t) of Compound I in the range of about 10% to about400%, about 15% to about 300%, or about 20% to about 250% when CompoundI is taken with food compared to the same amount of Compound I takenduring a fasted condition. In some further embodiments, the increase inAUC_(0-t) of Compound I is in the range of 20% to about 200%, about 25%to about 150%, or about 30% to about 125%. In one embodiment, theincrease in AUC_(0-t) of Compound I is about 37%. In another embodiment,the increase in AUC_(0-t) is about 49%. In yet another embodiment, theincrease in AUC_(0-t) is about 114%.

In some such embodiments, the increase in bioavailability comprises anincrease in AUC_(0- ∞)of Compound I in the range of about 10% to about400%, about 15% to about 300%, or about 20% to about 250% when CompoundI is taken with food compared to the same amount of Compound I takenduring a fasted condition. In some further embodiments, the increase inAUC_(0-∞)of Compound I is in the range of 20% to about 200%, about 25%to about 150%, or about 30% to about 125%. In one embodiment, theincrease in AUC_(0-∞)of Compound I is about 35%. In another embodiment,the increase in AUC_(0-∞)is about 46%. In yet another embodiment, theincrease in AUC_(0-∞)is about 103%.

Some embodiments of the present disclosure relate to methods ofproviding Compound I therapy to a subject, comprising providing atherapeutically effective amount of Compound I to the subject; andadvising the subject not to take a proton pump inhibitor (PPI)concomitantly with Compound I. Some other embodiments of the presentdisclosure relate to methods of providing Compound I therapy to asubject, comprising providing a therapeutically effective amount ofCompound I to the subject; and advising the subject not to take a protonpump inhibitor (PPI) prior to or subsequent to taking Compound I. Someembodiments of the present disclosure relate to methods of providingCompound I therapy to a subject, comprising providing a therapeuticallyeffective amount of Compound I to the subject; and advising the subjectnot to take a proton pump inhibitor (PPI) concomitantly with Compound I,wherein the PPI causes a 24-hour intra-gastric pH of 4 or above. In someembodiments, PPIs should be avoided during Compound I therapy includethose that cause a 24-hour mean intra-gastric pH of equal or over about6.0, 5.9, 5.8, 5.7, 5.6, 5.5, 5.4, 5.3, 5.2, 5.1, 5.0, 4.9, 4.8, 4.7,4.6, 4.5, 4.4, 4.3, 4.2, 4.1, 4.0, 3.9, 3.8, 3.7, 3.6, 3.6, 3.5, 3.4,3.3, 3.2, 3.1, 3.0, 2.9, 2.8, 2.7, 2.6, 2.5, 2.4, 2.3, 2.2, 2.1, 2.0,1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, or 1.0, or a range definedby any of the two preceding values. In one embodiment, PPIs causing a24-hour mean intra-gastric pH of equal or over 4.0 should be avoided. Inanother embodiment, PPIs causing a 24-hour mean intra-gastric pH ofequal or over 3.0 should be avoided. In one embodiment, the PPI israbeprazole. In some embodiments, the methods further comprise advisingthe subject to take Compound I with food.

Some further embodiments of the present disclosure relate to methods forproviding Compound I therapy, comprising administering a therapeuticallyeffective amount of Compound I to a subject having an intra-gastric pHequal to or less than 4.0, 3.5, 3.0, 2.5, 2.0, 1.5, or 1.0, or a rangedefined by any of the two preceding values. Some further embodiments ofthe present disclosure relate to methods for providing Compound Itherapy, comprising administering a therapeutically effective amount ofCompound I to a subject having an intra-gastric pH equal to or less than3.0. Some further embodiments of the present disclosure relate tomethods for providing Compound I therapy, comprising administering atherapeutically effective amount of Compound I to a subject having anintra-gastric pH equal to or less than 2.0. In some such embodiments,the intra-gastric pH is the mean 24-hour intra-gastric pH. In some otherembodiment, the intra-gastric pH is measured as the mean 12-hourintra-gastric pH, mean 8-hour intra-gastric pH, mean 6-hourintra-gastric pH, or mean 4-hour intra-gastric pH. In any of theembodiments described herein, Compound I may be administered with food.

Some further embodiments of the present disclosure relate to methods ofproviding Compound I therapy to a subject, comprising evaluating therenal function of the subject; and administering a therapeuticallyeffective amount of Compound I to the subject. The purpose of thisevaluation is to determine the renal effect of Compound I, for example,whether Compound I therapy would likely cause any kidney injury.

Acute kidney injury (AKI) is defined by Kidney Disease Improving GlobalOutcomes (KDIGO) (Kidney International Supplements (2012) 2, 8-12) asany of the following: increase in serum creatinine (SCr)≥0.3 mg/dL(≥26.5 μmol/L) within 48 hours; or increase in SCr to ≥1.5 timesbaseline, which is known or presumed to have occurred within the prior 7days; or urine volume <0.5 mL/kg/h for 6 hours. AKI is staged forseverity according to the following criteria.

Stage Serum creatinine (SCr) Urine output 1 1.5-1.9 times baseline <0.5mL/k/h for 6-12 h OR ≥0.3 mg/dL (≥26.5 μmol/L) increase 2 2-2.9 timesbaseline <0.5 mL/kg/h for ≥12 h 3 3 times baseline <0.3 mL/kg/h for ≥24h OR OR Increase in SCr ≥4 mg/dL Anuria for ≥12 h (≥353.6 μmol/L) ORInitiation of renal replacement therapy OR In patients <18 years,decrease in eGFR to <35 mL/min per 1.73 m²

In some embodiments, evaluating the renal function of the subjectcomprises determining the subject's creatinine clearance rate. In someembodiments, the subject's creatinine clearance rate is evaluated priorto administering the therapeutically effective amount of Compound I tothe subject. In some embodiments, the subject's creatinine clearancerate is evaluated after administering the therapeutically effectiveamount of Compound I to the subject. In some embodiments, the subject'screatinine clearance rate is evaluated prior to and after administeringthe therapeutically effective amount of Compound I to the subject. Insome such embodiments, the subject has a creatinine clearance of ≥90mL/min. In some other embodiments, the subject has a creatinineclearance of 60-89 mL/min. In some further embodiments, the subject hasa creatinine clearance of 30-59 mL/min. In still some furtherembodiments, the subject has a creatinine clearance of 15-29 mL/min. Insome embodiments, the subject does not have end stage renal disease(ESRD) requiring dialysis or have renal failure. In some embodiments,the method further comprises monitoring changes in the subject's serumcreatinine (Scr) level after the administering of Compound I. In somefurther embodiments, the increase in the subject's Scr afteradministration of Compound I is monitored. In one particular embodiment,an increase in the subject's Scr ≥0.3 mg/dL from baseline is measured.In another embodiment, a percent increase in the subject's Scr ≥30% frombaseline is measured. In some embodiments, the methods further comprisesadjusting the amount of Compound I or discontinuing Compound I therapy,for example, if the percent change in the subject's Scr from baseline isover 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%,150%, 160%, 170%, 180%, 190%, or 200%. Alternatively, adjusting theamount of Compound I or discontinuing Compound I therapy may be requiredif the increase in the subject's Scr from baseline is over 0.3, 0.4,0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.2, 1.4, 1.6, 1.8, 2.0, 2.2, 2.4, 2.6,2.8, 3.0, 3.2, 3.4, 3.6, 3.8, or 4.0 mg/dL. In some embodiments, themethods further comprise advising the subject to discontinue Compound Itherapy.

Some further embodiments of the present disclosure relate to methods ofproviding an anti-fibrotic therapy to a subject, comprising evaluatingthe renal function of the subject; advising the subject to not takeCompound I; and providing anti-fibrotic therapy other than Compound I.In some embodiments, the subject's renal function is evaluated prior toproviding an anti-fibrotic therapy to a subject. In some embodiments,the subject's renal function is evaluated after providing ananti-fibrotic therapy to a subject. In some embodiments, the subject'srenal function is evaluated prior to and after providing ananti-fibrotic therapy to a subject.

In any embodiment of the methods described herein, the subject issuffering from a fibrotic disorder. In one particular embodiment, thesubject is suffering from idiopathic pulmonary fibrosis (IPF).

Some additional embodiments of the present disclosure relate to kitscomprising a pharmaceutical composition, prescribing information, and acontainer, wherein the pharmaceutical composition comprises atherapeutically effective amount of Compound I. In some embodiments, theprescribing information advises a subject to take the pharmaceuticalcomposition with food. In some further embodiments, the prescribinginformation advises the subject not to take a proton pump inhibitor(PPI) concomitantly with Compound I. In one embodiment, the prescribinginformation advises to avoid PPIs causing a 24-hour mean intra-gastricpH of equal or over 4.0. In another embodiment, the prescribinginformation advises to avoid PPIs causing a 24-hour mean intra-gastricpH of equal or over 3.0. In one embodiment, the PPI is selected fromomeprazole, lansoprazole, pantoprazole, esomeprazole, rabeprazole, anddexlansoprazole. In one embodiment, the PPI is rabeprazole. The kit mayinclude one or more unit dosage forms comprising Compound I. The unitdosage forms may be of an oral formulation. For example, the unit dosageforms may comprise pills, tablets, or capsules. The kit may include aplurality of unit dosage forms. In some embodiments, the unit dosageforms are in a container. In some embodiments, the dosage forms aresingle oral dosage forms comprising Compound I or pharmaceuticallyacceptable salts thereof. In some further embodiments, the prescribinginformation advises a health care provider to monitor for abnormalitiesand/or adverse reactions and consider dosage modification ordiscontinuation as needed in a subject with renal impairment. In someembodiments, abnormalities and/or adverse reactions comprise lab valuesoutside the range of normal. In some embodiments, the lab value outsidethe range of normal is creatinine clearance. In some embodiments, thelab value outside the range of normal is serum creatinine. In someadditional embodiments, the prescribing information advises a healthcare provider to not administer the pharmaceutical composition to asubject with end stage renal disease requiring dialysis. In some furtheradditional embodiments, the prescribing information advises a healthcare provider that no dose adjustment is necessary in patients with mildrenal impairment. In some further additional embodiments, theprescribing information advises a health care provider that thepharmaceutical composition should be used with caution in patients withmoderate to severe renal impairment. In some further additionalembodiments, the prescribing information advises a health care providerthat the pharmaceutical composition should be used with caution inpatients with moderate renal impairment. In some further additionalembodiments, the prescribing information advises a health care providerto not administer the pharmaceutical composition to a subject withsevere renal impairment.

The methods, compositions and kits disclosed herein may includeinformation. The information may be in a form prescribed by agovernmental agency regulating the manufacture, use, or sale ofpharmaceuticals, which notice is reflective of approval by the agency ofthe form of the drug for human or veterinary administration. Suchinformation, for example, may be the labeling approved by the U.S. Foodand Drug Administration for prescription drugs, or the approved productinsert. The information can include required information regarding doseand dosage forms, administration schedules and routes of administration,adverse events, contraindications, warning and precautions, druginteractions, and use in specific populations (see, e.g., 21 C.F.R. §201.57 which is incorporated herein by reference in its entirety), andin some embodiments is required to be present on or associated with thedrug for sale of the drug. In some embodiments, a kit is for sale of aprescription drug requiring the approval of and subject to theregulations of a governmental agency, such as the Food and DrugAdministration of the United States. In some embodiments, the kitcomprises the label or product insert required by the agency, such asthe FDA, for sale of the kit to consumers, for example in the U.S. Inpreferred embodiments, the information instructs an individual to takeCompound I, with food, preferably a meal. The information may alsoinstruct an individual to avoid taking a proton pump inhibitorconcomitantly, prior to or subsequent to taking Compound I. In someembodiments the information instructs a health care provider to monitorfor abnormalities and/or adverse reactions and consider dosagemodification or discontinuation as needed in a subject with renalimpairment and/or not administer Compound I to a subject with end stagerenal disease requiring dialysis. In some embodiments the informationinstructs a health care provider to monitor for abnormalities and/oradverse reactions and that no dose adjustment is necessary in patientswith mild renal impairment. In some embodiments the informationinstructs a health care provider to monitor for abnormalities and/oradverse reactions and that Compound I should be used with caution inpatients with moderate to severe renal impairment. In some embodimentsthe information instructs a health care provider to monitor forabnormalities and/or adverse reactions and that Compound I should beused with caution in patients with moderate renal impairment. In someembodiments the information instructs a health care provider to monitorfor abnormalities and/or adverse reactions and not administer thepharmaceutical composition to a subject with severe renal impairment.

Some embodiments include information, preferably printed, that takingCompound I with food results in an increase in the bioavailability ofCompound I or a pharmaceutically acceptable salt thereof compared totaking the same amount of Compound I or a pharmaceutically acceptablesalt thereof without food.

Instructions and/or information may be present in a variety of forms,including printed information on a suitable medium or substrate (e.g., apiece or pieces of paper on which the information is printed), computerreadable medium (e.g., diskette, CD, etc. on which the information hasbeen recorded), or a website address that may be accessed via theinternet. Printed information may, for example, be provided on a labelassociated with a drug product, on the container for a drug product,packaged with a drug product, or separately given to the patient apartfrom a drug product, or provided in manner that the patient canindependently obtain the information (e.g., a website). Printedinformation may also be provided to a medical caregiver involved intreatment of the patient. In some embodiments, the information isprovided to a person orally.

Some embodiments comprise a therapeutic package suitable for commercialsale. Some embodiments comprise a container. The container can be in anyconventional shape or form as known in the art which is made of apharmaceutically acceptable material, for example a paper or cardboardbox, a glass or plastic bottle or jar, a re-sealable bag (e.g., to holda “refill” of tablets for placement into a different container), or ablister pack with individual dosages for pressing out of the packaccording to a therapeutic schedule. The container employed can dependon the exact dosage form involved, e.g., a conventional cardboard boxwould not generally be used to hold a liquid suspension. It is feasiblethat more than one container can be used together in a single package tomarket a single dosage form. For example, tablets may be contained in abottle which is in turn contained within a box.

The information can be associated with the container, for example, bybeing: written on a label (e.g., the prescription label or a separatelabel) adhesively affixed to a bottle containing a dosage form describedherein; included inside a container as a written package insert, such asinside a box which contains unit dose packets; applied directly to thecontainer such as being printed on the wall of a box; or attached as bybeing tied or taped, e.g., as an instructional card affixed to the neckof a bottle via a string, cord or other line, lanyard or tether typedevice. The information may be printed directly on a unit dose pack orblister pack or blister card.

Pharmaceutical Compositions

Some embodiments include pharmaceutical compositions comprising: (a) asafe and therapeutically effective amount of Compound I described herein(including polymorphs, and solvates thereof), or pharmaceuticallyacceptable salts thereof; and (b) a pharmaceutically acceptable carrier,diluent, excipient or combination thereof.

The compounds useful as described above can be formulated intopharmaceutical compositions for use in treatment of various conditionsor disorders. Standard pharmaceutical formulation techniques are used,such as those disclosed in Remington's The Science and Practice ofPharmacy, 21st Ed., Lippincott Williams & Wilkins (2005), incorporatedby reference in its entirety.

In addition to the selected compound useful as described above, someembodiments include compositions containing apharmaceutically-acceptable carrier. The term“pharmaceutically-acceptable carrier”, as used herein, means one or morecompatible solid or liquid filler diluents or encapsulating substances,which are suitable for administration to a mammal. The term“compatible”, as used herein, means that the components of thecomposition are capable of being commingled with the subject compound,and with each other, in a manner such that there is no interaction,which would substantially reduce the pharmaceutical efficacy of thecomposition under ordinary use situations. Pharmaceutically-acceptablecarriers must, of course, be of sufficiently high purity andsufficiently low toxicity to render them suitable for administrationpreferably to an animal, preferably mammal being treated.

Pharmaceutically-acceptable carriers include, for example, solid orliquid fillers, diluents, hydrotropies, surface-active agents, andencapsulating substances. Some examples of substances, which can serveas pharmaceutically-acceptable carriers or components thereof, aresugars, such as lactose, glucose and sucrose; starches, such as cornstarch and potato starch; cellulose and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powderedtragacanth; malt; gelatin; talc; solid lubricants, such as stearic acidand magnesium stearate; calcium sulfate; vegetable oils, such as peanutoil, cottonseed oil, sesame oil, olive oil, corn oil and oil oftheobroma; polyols such as propylene glycol, glycerine, sorbitol,mannitol, and polyethylene glycol; alginic acid; emulsifiers, such asthe TWEENS; wetting agents, such sodium lauryl sulfate; coloring agents;flavoring agents; tableting agents, stabilizers; antioxidants;preservatives; pyrogen-free water; isotonic saline; and phosphate buffersolutions.

Optional pharmaceutically-active materials may be included, which do notsubstantially interfere with the inhibitory activity of the compound.The amount of carrier employed in conjunction with the compound issufficient to provide a practical quantity of material foradministration per unit dose of the compound. Techniques andcompositions for making dosage forms useful in the methods describedherein are described in the following references, all incorporated byreference herein: Modern Pharmaceutics, 4th Ed., Chapters 9 and 10(Banker & Rhodes, editors, 2002); Lieberman et al., PharmaceuticalDosage Forms: Tablets (1989); and Ansel, Introduction to PharmaceuticalDosage Forms 8th Edition (2004).

Various oral dosage forms can be used, including such solid forms astablets, capsules, granules and bulk powders. Tablets can be compressed,tablet triturates, enteric-coated, sugar-coated, film-coated, ormultiple-compressed, containing suitable binders, lubricants, diluents,disintegrating agents, coloring agents, flavoring agents, flow-inducingagents, and melting agents. Liquid oral dosage forms include aqueoussolutions, emulsions, suspensions, solutions and/or suspensionsreconstituted from non-effervescent granules, and effervescentpreparations reconstituted from effervescent granules, containingsuitable solvents, preservatives, emulsifying agents, suspending agents,diluents, sweeteners, melting agents, coloring agents and flavoringagents.

The pharmaceutically-acceptable carriers suitable for the preparation ofunit dosage forms for peroral administration is well-known in the art.Tablets typically comprise conventional pharmaceutically-compatibleadjuvants as inert diluents, such as calcium carbonate, sodiumcarbonate, mannitol, lactose and cellulose; binders such as starch,gelatin and sucrose; disintegrants such as starch, alginic acid andcroscarmelose; lubricants such as magnesium stearate, stearic acid andtalc. Glidants such as silicon dioxide can be used to improve flowcharacteristics of the powder mixture. Coloring agents, such as the FD&Cdyes, can be added for appearance. Sweeteners and flavoring agents, suchas aspartame, saccharin, menthol, peppermint, and fruit flavors, areuseful adjuvants for chewable tablets. Capsules typically comprise oneor more solid diluents disclosed above. The selection of carriercomponents depends on secondary considerations like taste, cost, andshelf stability, which are not critical, and can be readily made by aperson skilled in the art.

Per-oral compositions also include liquid solutions, emulsions,suspensions, and the like. The pharmaceutically-acceptable carrierssuitable for preparation of such compositions are well known in the art.Typical components of carriers for syrups, elixirs, emulsions andsuspensions include ethanol, glycerol, propylene glycol, polyethyleneglycol, liquid sucrose, sorbitol and water. For a suspension, typicalsuspending agents include methyl cellulose, sodium carboxymethylcellulose, AVICEL RC-591, tragacanth and sodium alginate; typicalwetting agents include lecithin and polysorbate 80; and typicalpreservatives include methyl paraben and sodium benzoate. Peroral liquidcompositions may also contain one or more components such as sweeteners,flavoring agents and colorants disclosed above.

Such compositions may also be coated by conventional methods, typicallywith pH or time-dependent coatings, such that the subject compound isreleased in the gastrointestinal tract in the vicinity of the desiredtopical application, or at various times to extend the desired action.Such dosage forms typically include, but are not limited to, one or moreof cellulose acetate phthalate, polyvinylacetate phthalate,hydroxypropyl methyl cellulose phthalate, ethyl cellulose, Eudragitcoatings, waxes and shellac.

Compositions described herein may optionally include other drug actives.

It will be understood by those of skill in the art that numerous andvarious modifications can be made without departing from the spirit ofthe present invention. Therefore, it should be clearly understood thatthe embodiments of the present invention disclosed herein areillustrative only and are not intended to limit the scope of the presentinvention. Any reference referred to herein is incorporated by referencefor the material discussed herein, and in its entirety.

EXAMPLE

A Phase 1, randomized, blinded, placebo-controlled safety, tolerability,and pharmacokinetic study of Compound I in 80 healthy adult subjects wasconducted.

Methodology

This study was a randomized, blinded, placebo-controlled, ascending-dosestudy to evaluate the safety, tolerability, and pharmacokinetic (PK) ofsingle (Part A) and multiple (Part B) doses of Compound I in healthysubjects. In addition, the effects of a standard high-fat breakfast,standard low-fat breakfast, and pretreatment and co-administration of aproton pump inhibitor (PPI) on the tolerability and PK of a single doseof Compound I were investigated in 2 groups in Part A. All subjectsreceived their full dose of Compound I, administered as the appropriatenumber of either 25 or 200 mg tablets. The high fat breakfast comprisedthe following: total energy: 895 kcal; total fat: 61 g; total protein:41 g; total carbohydrate: 46 g. The low fat breakfast comprised thefollowing: total energy: 611 kcal; total fat: 14.7 g; total protein:20.3 g; total carbohydrate: 106.3 g.

Part A—Single Ascending Dose (SAD):

In Part A, 56 subjects were studied in 6 groups (Groups A1 to A6) witheach of Groups A1, A2, A3, A5, and A6 composed of 8 subjects (6 receivedCompound I, 2 received placebo) and Group A4 was composed of 16 subjects(12 received Compound I, 4 received placebo). The first dose group (A1)included a sentinel cohort of 2 subjects (1 subject received Compound Iand 1 subject received placebo) dosed 48 hours in advance of theremainder of the group.

All subjects in Groups A1 through A6 participated in Treatment Period 1and received the fasted treatment regimen. In Treatment Period 1,subjects resided at the Clinical Research Unit (CRU) from Day −1 (theday before dosing) to Day 4 (72 hours post-dose). In Treatment Period 1,all doses were administered on the morning of Day 1, after an overnightfast of at least 8 hours. In Groups A1, A2, A3, and A6, each subjectreceived only a single dose of Compound I (25 mg in Group A1, 75 mg inGroup A2, 200 mg in Group A3, and 1600 mg in Group A6) or placebo (perthe randomization schedule) during the study.

For Group A4, doses (400 mg Compound I or placebo) during TreatmentPeriod 1 were administered in a fasted state on the morning of Day 1.Doses in Treatment Period 2 were administered 30 minutes after starting,and within approximately 10 minutes of completing, a high-fat standardbreakfast on the morning of Day 1. Doses during Treatment Period 3 wereadministered 30 minutes after starting, and within approximately 10minutes of completing a low-fat standard meal on the morning of Day 1.Doses during Treatment Period 4 were administered on Day 1 after anovernight fast and following administration of a PPI (rabeprazole 20 mg)for 3 days (given as 3 daily [QD] doses, with the final PPI dose at 2hours prior to study drug administration on Day 1). Subjects in Group A4received the same Compound I or placebo treatment in all treatmentperiods, such that each subject received up to 4 single doses ofCompound I or placebo.

For Group A5, doses (800 mg Compound I or placebo) during TreatmentPeriod 1 were administered in a fasted state on the morning of Day 1,doses during Treatment Period 2 were administered 30 minutes afterstarting a low-fat standard breakfast on the morning of Day 1, and dosesduring Treatment Period 3 were administered on Day 1 after a low-fatmeal and following administration of a PPI (rabeprazole 20 mg) for 3days (given as 3 QD doses, with the final PPI dose at 2 hours prior tostudy drug administration on Day 1). Subjects in Group A5 received thesame Compound I or placebo treatment in all treatment periods, such thateach subject received up to 3 single doses of Compound I or placebo.

For Group A4, each subject participated in 3 additional treatmentperiods, each separated by a minimum of 7 days. Group A4 resided at theCRU from Day −1 to Day 4 of Treatment Periods 2, 3, and 4. For Group A5,each subject participated in 2 additional treatment periods, eachseparated by a minimum of 7 days. Group A5 resided at the CRU from Day−1 to Day 4 of Treatment Periods 2 and 3. All subjects returned for aFollow-up visit between 5 to 14 days after their final dose of studytreatment.

In Part A, all doses in Treatment Period 1 were administered after anovernight fast of at least 8 hours. For the A4 cohort, in TreatmentPeriods 2 and 3, doses were administered 30 minutes after starting andapproximately 10 minutes after completing a high- or low-fat breakfast.In Treatment Period 4, the dose was administered after an overnight fastand following administration of a PPI (PPI was comprised of 3 doses ofrabeprazole 20 mg, starting on Day −2 and with the final dose 2 hoursbefore Compound I administration on Day 1). For Group A5, doses duringTreatment Period 2 were administered 30 minutes after starting andapproximately 10 minutes after completing a low-fat standard breakfaston the morning of Day 1, and doses during Treatment Period 3 wereadministered on Day 1 after a low-fat meal and following administrationof a PPI for 3 days (given as 3 QD doses, with the final PPI dose at 2hours prior to study drug administration on Day 1).

A summary of the PK parameters of Compound I following single doseadministration in the fasted state are summarized in Table 1.

TABLE 1 Mean Pharmacokinetic Parameters of Compound I by Treatment Group(Part A - Single Doses Administered in the Fasting State) Dose ofCompound I 25 mg (A1) 75 mg (A2) 200 mg (A3) 400 mg (A4) Parameter (N =6) (N = 6) (N = 6) (N = 12) AUC_(0-t) (hr*ng/mL) 4550 (26.0) 13000(16.3) 32300 (31.3) 53800 (23.2) AUC_(0-t (norm)) 13400 (25.2) 12600(31.8) 12000 (33.6) 9420 (31.0) (hr*ng/mL/(mg/kg)) AUC_(0-∞) 4600 (25.7)13000 (16.1) 32600 (31.1) 55100 (23.0) (hr*ng/mL) AUC_(0-∞ (norm)) 13600(24.9) 12600 (31.6) 12100 (33.5) 9650 (30.0) (hr*ng/mL/(mg/kg)) %AUC_(extrap) ^(a) (%) 1.25 (0.493) 0.486 (0.248) 0.969 (0.434) 2.37(2.83) C_(max) (ng/mL) 913 (28.0) 2250 (17.1) 3060 (31.9) 4510 (13.1)C_(max (norm)) 2700 (29.8) 2180 (31.4) 1140 (30.1) 790 (16.3)(ng/mL/(mg/kg)) t_(max) ^(b) (hr) 1.50 (1.00-2.50) 1.25 (1.00-2.00) 1.75(1.00-6.00) 2.50 (1.00-4.25) t_(1/2) (hr) 3.61 (43.8) 5.02 (42.1) 10.2(14.5)^(c) 11.7 (54.5) λ_(Z) (hr⁻¹) 0.192 (43.8) 0.138 (42.1) 0.0602(34.0) 0.0594 (54.5) CL/F (mL/min) 90.5 (25.7) 96.0 (16.1) 102 (31.1)121 (23.0) CL/F_((norm)) 1.23 (24.9) 1.32 (31.6) 1.38 (33.5) 1.73 (30.0)((mL/min)/kg) V_(z/)F (L) 28.3 (49.9) 41.7 (53.8) 102 (51.2) 122 (54.1)V_(z/)F_((norm)) (L/kg) 0.384 (49.6) 0.574 (64.0) 1.37 (56.0) 1.74(64.8) Ae₀₋₂₄ (mg) 19.2 (8.7) 54.8 (6.8) 105 (21.3) 133 (12.4) fe₀₋₂₄(%) 76.9 (8.7) 73.0 (6.8) 52.5 (21.3) 33.3 (12.4) CL_(g) (mL/min) 70.5(32.0) 71.8 (19.7) 63.5 (36.7) 49.7 (21.2) Dose of Compound I 800 mg(A5) 1600 mg (A6) Parameter (N = 6) (N = 6) AUC_(0-t) (hr*ng/mL) 74500(27.1) 73600 (47.6) AUC_(0-t (norm)) 6700 (35.4) 3090 (41.4)(hr*ng/mL/(mg/kg)) AUC_(0-∞) 78700 (29.7) 86900 (61.2)^(d) (hr*ng/mL)AUC_(0-∞ (norm)) 7080 (38.0) 3740 (51.2)^(d) (hr*ng/mL/(mg/kg)) %AUC_(extrap) ^(a) (%) 5.17 (6.34) 6.57 (4.04)^(d) C_(max) (ng/mL) 5910(27.2) 5580 (37.0) C_(max (norm)) 532 (28.9) 235 (32.5) (ng/mL/(mg/kg))t_(max) ^(b) (hr) 1.75 (1.50-4.00) 2.00 (1.00-4.00) t_(1/2) (hr) 11.3(44.6)^(d) 19.8 (25.8)^(d) λ_(Z) (hr⁻¹) 0.0433 (70.8) 0.0351 (25.8)^(d)CL/F (mL/min) 169 (29.7) 307 (61.2)^(d) CL/F_((norm)) 2.35 (38.0) 4.46(51.2)^(d) ((mL/min)/kg) V_(z/)F (L) 234 (46.9) 525 (47.8)^(d)V_(z/)F_((norm)) (L/kg) 3.26 (49.8) 7.62 (39.1)^(d) Ae₀₋₂₄ (mg) 172(23.0) 145 (16.2) fe₀₋₂₄ (%) 21.5 (23.0) 9.09 (16.2) CL_(g) (mL/min)48.5 (32.3) 47.6 (50.5) Ae₀₋₂₄ = amount of GDC-3280 excreted over 24hours; AUC_(0-t) = area under the concentration-time curve (AUC) fromtime 0 to the last quantifiable concentration; AUC_(0-∞) = AUCextrapolated to infinity; % AUC_(extrap) = percentage of AUC that is dueto extrapolation from the last measurable concentration to infinity;C_(max) = maximum observed plasma concentration; CL/F = apparent totalplasma clearance; CL_(g) = renal clearance; CV % = coefficient ofvariation; fe₀₋₂₄ = percentage of GDC-3280 excreted over 24 hours; N =number of subjects; norm = body weigh-normalized value; t_(max) = timeto maximum concentration; t_(1/2) = apparent terminal eliminationhalf-life; V_(z/)F = apparent volume of distribution during the terminalelimination phase; λ_(Z) = apparent terminal elimination rate constant.^(a)Arithmetic mean (arithmetic standard deviation). ^(b)Median(min-max). ^(c)n = 5. ^(d)n = 4.

Plasma concentration versus time plots for all doses were characterizedby a rapid absorption phase. Median tmax results were generally similaracross all doses, ranging from 1.3 to 2.5 hours, although there was atrend for increase in individual tmax ranges at the higher dose levels(200 to 1600 mg), with tmax occurring as late as 6 hours compared to thelatest time point of 2.5 hours observed across the 25 and 75 mg doses.The mean t1/2 was similar for the 25 and 75 mg doses with values of 3.6and 5.0 hours, respectively (range 2.1 to 9.6 hours), and increased to10.2, 11.7, and 11.3 hours (range 4.1 to 27.0 hours) at the 200, 400,and 800 mg doses, respectively. At the highest dose level of 1600 mg,geometric mean t1/2 was 19.8 hours (range 13.8 to 24.0 hours).

Dose-normalized PK parameters were analyzed using ANOVA. Increase insystemic exposure, based on AUC and Cmax, between the 2 lowest doselevels (25 and 75 mg) are consistent with linear PK, with a 3-foldincrease in dose resulting in 2.9-, 2.8-, and 2.5-fold increases inAUC0-t, AUC0-_(∞), and Cmax, respectively for dose and body weightnormalized AUC0-t, AUC0-_(∞), and Cmax, respectively. Between the higherdose levels of 200 to 800 mg, there was a trend for AUC and Cmax valuesto increase in a less than proportional manner. At the 800-mg doselevel, a 32.0-fold increase in dose resulted in 16.4-, 17.1-, and6.5-fold increases in AUC0-t, AUC0-_(∞), and Cmax, respectively.Following the 1600 mg dose, there was no significant increase in AUC andCmax compared to that of the 800 mg dose.

A summary of the PK parameters of Compound I following single doseadministration of 400 and 800 mg in the fed and fasted states and withrabeprazole (PPI) are presented in Table 2 below.

TABLE 2 Mean Pharmacokinetic Parameters of Compound I by TreatmentCondition (Part A - Single Doses) Dose of Compound I 400 mg (A4) (N =12) +20 mg Rabeprazole Fed, Fed, QD x 3 Parameter Fasted High-fatLow-fat Fasted AUC_(0-t) (hr*ng/mL) 53800 (23.2) 80200 (26.6) 73700(36.1) 46500 (19.9) AUC_(0-t (norm)) 9420 (31.0) 14000 (33.3) 12900(40.0) 8130 (29.0) (hr*ng/mL)/(mg/kg)) AUC_(0-∞) 55100 (23.0) 80300(26.5) 74200 (35.5) 48100 (19.0) (hr*ng/mL) AUC_(0-∞ (norm)) 9650 (30.0)14100 (33.3) 13000 (39.4) 8410 (27.0) (hr*ng/mL)/(mg/kg)) % AUC_(extrap)^(a) (%) 2.37 (2.83) 0.213 (0.114) 0.691 (0.659) 3.25 (4.03) C_(max)(ng/mL) 4510 (13.1) 7620 (11.0) 7420 (17.4) 3770 (19.3) C_(max (norm))790 (16.3) 1330 (17.7) 1300 (20.5) 660 (22.4) (ng/mL/(mg/kg)) t_(max)^(b) (hr) 2.50 (1.00-4.25) 3.50 (1.50-6.00) 2.50 (1.00-4.00) 2.50(1.50-4.00) t_(1/2) (hr) 11.7 (54.5) 8.05 (45.2) 7.52 (48.1)^(c) 10.5(62.8)^(c) λ_(Z) (hr⁻¹) 0.0594 (54.5) 0.0861 (45.2) 0.0852 (54.8) 0.0603(70.3) CL/F (mL/min) 121 (23.0) 83.0 (26.5) 89.8 (35.5) 139 (19.0)CL/F_((norm)) 1.73 (30.0) 1.19 (33.3) 1.28 (39.4) 1.98 (27.0)((mL/min)/kg) V_(z/)F (L) 122 (54.1) 57.8 (58.6) 63.3 (68.4) 138 (71.3)V_(z/)F_((norm)) (L/kg) 1.74 (64.8) 0.826 (68.5) 0.904 (77.5) 1.97(84.7) Dose of Compound I 800 mg (A5) (N = 6) +20 mg Rabeprazole Fed, QDx 3 Parameter Fasted Low-fat Fed, Low-fat AUC_(0-t) (hr*ng/mL) 74500(27.1) 159000 (36.4) 122000 (21.6) AUC_(0-t (norm)) 6700 (35.4) 14300(29.3) 11000 (29.9) (hr*ng/mL)/(mg/kg)) AUC_(0-∞) 78700 (29.7) 160000(36.5) 124000 (20.7) (hr*ng/mL) AUC_(0-∞ (norm)) 7080 (38.0) 14400(29.2) 11100 (29.7) (hr*ng/mL)/(mg/kg)) % AUC_(extrap) ^(a) (%) 5.17(6.34) 0.395 (0.410) 1.27 (2.08) C_(max) (ng/mL) 5910 (27.2) 13300(31.5) 10000 (28.7) C_(max (norm)) 532 (28.9) 1200 (21.7) 900 (34.5)(ng/mL/(mg/kg)) t_(max) ^(b) (hr) 1.75 (1.50-4.00) 3.00 (2.50-4.00) 3.00(2.50-4.00) t_(1/2) (hr) 11.3 (44.6)^(d) 8.74 (57.1) 8.92 (43.8)^(c)λ_(Z) (hr⁻¹) 0.0433 (70.8) 0.0793 (57.1) 0.0666 (57.1) CL/F (mL/min) 169(29.7) 83.3 (36.5) 108 (20.7) CL/F_((norm)) 2.35 (38.0) 1.16 (29.2) 1.50(29.7) ((mL/min)/kg) V_(z/)F (L) 234 (46.9) 63.0 (78.2) 97.2 (67.7)V_(z/)F_((norm)) (L/kg) 3.26 (49.8) 0.876 (79.8) 1.35 (61.6) AUC_(0-t) =area under the concentration-time curve (AUC) from time 0 to the lastquantifiable concentration; AUC_(0-∞) = AUC extrapolated to infinity; %AUC_(extrap) = percentage of AUC that is due to extrapolation from thelast measurable concentration to infinity; C_(max) = maximum observedplasma concentration; CL/F = apparent total plasma clearance; CL_(R) =renal clearance; t_(max) = time to maximum concentration; CV % =coefficient of variation; N = number of subjects; norm = bodyweigh-normalized value; t_(1/2) = apparent terminal eliminationhalf-life; V_(z/)F = apparent volume of distribution during the terminalelimination phase; λ_(Z) = apparent terminal elimination rate constant.^(a)Arithmetic mean (arithmetic standard deviation). ^(b)Median(min-max). ^(c)n = 11. ^(d)n = 4. ^(e)n = 5.

Food Effect

Following administration of 400 mg Compound I in the high-fat fed state,there was a delay in tmax of 1.0 hour (median tmax 3.5 hours, range 1.5to 6.0 hours) compared to that of the low-fat fed and fasted states(median tmax 2.5 hours, range 1.0 to 4.3 hours). See Table 2. Followingattainment of Cmax, plasma Compound I concentrations declined in abiphasic manner in both the fasted and fed states. Systemic exposure washigher in the high-fat fed state, with ratios of fed to fasted of149.0%, 145.8%, and 168.9% for AUC0-t, AUC0-_(∞), and Cmax, respectively(Table 3). Following a 400 mg Compound I dose in the low-fat fed statethere was an increase in systemic exposure with ratios of fed to fastedof 137.1%, 134.7%, and 164.4% in AUC0-t, AUC0-_(∞), and Cmax,respectively (Table 3). Statistical comparison of the high-fat tolow-fat fed state at 400 mg Compound I indicated similar exposure withratios of 108.7%, 108.2% and 102.7% for AUC0-t, AUC0-_(∞), and Cmax,respectively (Table 3).

Following administration of 800 mg Compound I in the low-fat fed state,the median tmax was delayed by 1.25 hours. Systemic exposure to CompoundI in the low-fat fed state, as measured by AUC0-t, AUC0-_(∞), and Cmaxincreased, with ratios of fed to fasted of 214.0%, 203.3%, and 225.5%,respectively (Table 3).

Following administration of both 400 and 800 mg Compound I there was atrend for a slightly longer t1/2 in the fasted state with geometric meant1/2 values of 11.7 and 11.3 hours, respectively. This is in comparisonto the high- and low-fat states where geometric means ranged from 7.5 to8.7 hours.

TABLE 3 Statistical Analysis of Pharmacokinetic Data of Compound I (PartA): Effect of High-fat, Low-fat and Fed States LS Means^(a) LS Means^(a)400 mg Compound I 400 mg Compound I Test/ 90% Confidence Fed, High-fatFasted Reference^(c) Interval^(d) CV_(W) ^(e) Parameters (Units) n^(b)(Test) n^(b) (Reference) (%) (%) (%) AUC_(0-t) (hr*ng/mL) 12 80200 1253800 149.0 (131.9, 168.4) 17.8 AUC_(0-∞) (hr*ng/mL) 12 80300 12 55100145.8 (129.3, 164.3) 17.5 C_(max) (ng/mL) 12 7620 12 4510 168.9 (151.8,187.9) 15.5 400 mg Compound I 400 mg Compound I Test/ 90% ConfidenceFed, Low-fat Fasted Reference^(c) Interval^(d) CV_(W) ^(e) Parameters(Units) n^(b) (Test) n^(b) (Reference) (%) (%) (%) AUC_(0-t) (hr*ng/mL)12 73700 12 53800 137.1 (121.3, 154.9) 17.;8 AUC_(0-∞) (hr*ng/mL) 1274200 12 55100 134.7 (119.5, 151.8) 17.5 C_(max) (ng/mL) 12 7420 12 4510164.4 (147.8, 182.9) 15.5 400 mg Compound I 400 mg Compound I Test/ 90%Confidence Fed, High-fat Fed, Low-fat Reference^(c) Interval^(d) CV_(w)^(e) Parameters (Units) n^(b) (Test) n^(b) (Reference) (%) (%) (%)AUC_(0-t) (hr*ng/mL) 12 80200 12 73700 108.7 (96.2, 122.9) 17.8AUC_(0-∞) (hr*ng/mL) 12 80300 12 74200 108.2 (96.0, 122.0) 17.5 C_(max)(ng/mL) 12 7620 12 7420 102.7 (92.3, 114.3) 15.5 400 mg Compound I 400mg Compound I Test/ 90% Confidence Fed, Low-fat Fasted Reference^(c)Interval^(d) CV_(W) ^(e) Parameters (Units) n^(b) (Test) n^(b)(Reference) (%) (%) (%) AUC_(0-t) (hr*ng/mL) 6 159000 6 74500 214.0(167.3, 273.7) 23.9 AUC_(0-∞) (hr*ng/mL) 6 160000 6 78700 203.3 (157.8,262.0) 24.6 C_(max) (ng/mL) 6 13300 6 5910 225.5 (181.0, 280.9) 21.2AUC_(0-t) = area under the concentration-time curve (AUC) from time 0 tothe last quantifiable concentration; AUC_(0-∞) = AUC extrapolated toinfinity; C_(max) = maximum observed plasma concentration; CV_(W) =within-subject coefficients of variation; LS = least squares. ^(a)Leastsquares means from analysis of variance, calculated by transforming thenatural-log means back to the linear scale (ie, geometric means). ^(b)nis the number of observations in each treatment used in the model.^(c)Ratio of parameter means for natural log-transformed parameter(expressed as a percentage). Natural log-transformed ratios transformedback to the linear scale. ^(d)90% confidence interval for ratio ofparameter means of natural log-transformed parameter (expressed as apercentage). Natural log-transformed confidence limits transformed backto the linear scale. ^(e)Within-subject coefficients of variationCV_(W)(%) = [exp(mse) − 1]^(1/2) × 100

Proton Pump Inhibitor (PPI) Effect

Following administration of a single 400 mg of Compound I in combinationwith 20 mg rabeprazole (QD×3) in the fasted state, Compound I wasrapidly absorbed with a median t_(max) of 2.5 hours (ranging from 1.5 to4.0 hours) similar to the results when 400 mg of Compound I wasadministered alone (median t_(max) was 2.5 hours, ranging from 1.0 to4.3 hours). After reaching C_(max), Compound I exhibited a biphasicdecline with a similar geometric mean t_(1/2) to that seen in the fastedstate alone, 10.5 hours and 11.7 hours, respectively.

When a single dose of 400 mg Compound I was administered in combinationwith rabeprazole (20 mg QD×3) in the fasted state there were decreasesin AUC_(0-t), AUC₀₋₂₈, and C_(max), with ratios of PPI co-administrationto non-PPI co-administration of 86.4%, 87.2%, and 83.6%, respectively,with the 90% CIs excluding 100% in all comparisons (Table 4). Thebetween-subject variability based on AUC_(0-t), AUC_(0-∞), and C_(max)was low following Compound I administration alone and whenco-administered with rabeprazole in the fasted state, ranging from 19.0%to 23.2% for AUCs and 13.1% to 19.3% for C_(max), respectively (Table2).

When a single dose of 800 mg Compound I was co-administered withrabeprazole (20 mg, QD×3) in the low-fat fed state, there were decreasesin AUC_(0-t), AUC_(0-∞), and C_(max), with ratios of PPIco-administration to non-PPI co-administration of 76.5%, 77.2%, and75.0%, respectively (Table 4). These results show increased gastric pH(reduced gastric acid) leads to some impairment in absorption ofCompound I. Time to maximum plasma concentration appeared delayedfollowing the co-administration with rabeprazole, with a median t_(max)of 3.0 hours (ranging from 2.5 to 4.0 hours) compared to 1.8 hours whenadministered alone (ranging from 1.5 to 4.0 hours).

TABLE 4 Statistical Analysis of Pharmacokinetic Data of Compound I (PartA): PPI Effect LS Means^(a) 400 mg Compound I LS Means^(a) Fasted + 20mg 400 mg Compound I Test/ 90% Confidence Rabeprazole QD x 3 FastedReference^(c) Interval^(d) CV_(W) ^(e) Parameters (Units) n^(b) (Test)n^(b) (Reference) (%) (%) (%) AUC_(0-t) (hr*ng/mL) 12 46500 12 5380086.4 (76.5, 97.6) 17.8 AUC_(0-∞) (hr*ng/mL) 12 48100 12 55100 87.2(77.4, 98.3) 17.5 C_(max) (ng/mL) 12 3770 12 4510 83.6 (75.2, 93.0) 15.5800 mg Compound I Fed, Low-fat + 20 mg 800 mg Compound I Test/ 90%Confidence Rabeprazole QD x 3 Fasted Reference^(c) Interval^(d) CV_(W)^(e) Parameters (Units) n^(b) (Test) n^(b) (Reference) (%) (%) (%)AUC_(0-t) (hr*ng/mL) 6 122000 6 159000 76.5 (59.8, 97.9) 23.9 AUC_(0-∞)(hr*ng/mL) 6 124000 6 160000 77.2 (59.9, 99.5) 24.6 C_(max) (ng/mL) 610000 6 13300 75.0 (60.2, 93.5) 21.2 AUC_(0-t) = area under theconcentration-time curve (AUC) from time 0 to the last quantifiableconcentration; AUC_(0-∞) = AUC extrapolated to infinity; C_(max) =maximum observed plasma concentration; CV_(W) = within-subjectcoefficients of variation; LS = least squares. ^(a)Least squares meansfrom analysis of variance, calculated by transforming the natural-logmeans back to the linear scale (ie, geometric means). ^(b)n is thenumber of observations in each treatment used in the model. ^(c)Ratio ofparameter means for natural log-transformed parameter (expressed as apercentage). Natural log-transformed ratios transformed back to thelinear scale. ^(d)90% confidence interval for ratio of parameter meansof natural log-transformed parameter (expressed as a percentage).Natural log-transformed confidence limits transformed back to the linearscale. ^(e)Within-subject coefficients of variation CV_(W)(%) =[exp(mse) − 1]^(1/2) × 100

Part B—Multiple Ascending Dose (MAD):

In Part B, 24 subjects were studied in 3 groups (Groups B1 to B3), witheach group consisting of 8 subjects (6 received Compound I and 2received placebo). The dose, dosing frequency, duration, and dietarystate for Part B were determined based on review of available PK,safety, and tolerability data from Parts A and B.

All doses in Part B were administered following administration of alow-fat meal. In Groups B1 and B3, Compound I (200 mg for Group B1, 275mg for Group B3) or placebo was administered twice daily (BID) on Days 1to 6 and once on the morning of Day 7. In Group B2, subjects received QDdosing with 525 mg Compound I or placebo on Days 1 to 7.

In Part B, each subject participated in 1 treatment period. Subjectsresided at the CRU from Day −1 (the day before dosing) until the morningof Day 10 (72 hours after the final dose on Day 7). All subjectsreturned for a Follow-up visit between 5 to 14 days after their finaldose.

In Part B, all doses were administered after a low-fat meal. On Day 1and Day 7 (days with post-dose PK sampling), subjects started a low-fatbreakfast 30 minutes prior to dosing and were given 15 minutes tocomplete their meal; dosing occurred approximately 15 minutes aftercompletion of breakfast. On dosing Days 2 through 6, subjects were tocomplete their breakfast within an hour prior to dosing. For the eveningdoses, subjects were given a standard meal and completed their mealbetween 1 and 2 hours prior to dosing.

Following single and multiple dose administration of Compound I at 200mg BID, 275 mg BID, and 525 mg QD, Compound I was absorbed readily withmedian t_(max) values of 2.3 to 3.5 hours post-dose on Day 1 and 2.8 to4.0 hours post-dose on Day 7. On Day 7 plasma concentrations of CompoundI declined in a generally biphasic manner following the attainment ofC_(max), with t_(1/2) geometric mean values at the 200- and 275-mg BIDdose levels of 4.9 hours (individual values ranging from 3.5 to 6.3hours) and 5.6 hours (individual values ranging from 3.6 to 12.1 hours),respectively, and 6.3 hours (individual values ranging from 3.7 to 11.2hours) at 525 mg QD (Table 5).

There was an approximately dose-proportional increase in AUC_(0-∞)between the 200 mg BID and 525 mg QD dosing regimens, with a 2.6-foldincrease in dose resulting in a 2.5-fold increase in geometric meanAUC_(0-∞). For the 200- and 275-mg BID doses, there was a 1.2-foldincrease in geometric mean C_(max) for the 1.4-fold increase in dose.Following multiple administrations of 200 and 275 mg BID and 525 mg QD,steady-state plasma concentrations of Compound I were generally achievedwithin 2 days. On Day 7, following multiple BID dosing, there was someevidence of accumulation of Compound I, with a geometric mean RA_(AUC)value of 1.1 following a 200 mg BID dose (ranging from 0.9 to 1.3), 1.5(ranging from 1.1 to 1.9) at the 275-mg BID dose level, and 1.3 (range1.0 to 1.6) at the 525-mg QD dose level. As expected for differingdosing regimens, higher trough concentrations were attained for BIDdosing regimens compared to the QD regimen, with mean pre-dose CompoundI concentrations on Day 7 being 1680, 3260, and 897 ng/mL for 200 mgBID, 275 mg BID, and 525 mg QD doses, respectively.

TABLE 5 Mean Pharmacokinetic Parameters of Compound I by Treatment Group(Part B - Multiple Doses Administered Following a Low-fat Meal) Dose ofCompound I 200 mg BID (B1) 525 mg QD (B2) (N = 6) (N = 6) Parameter Day1 Day 7 Day 1 Day 7 AUC_(0-τ) (hr*ng/mL) 34900 (29.5)^(a) 38800 (27.3)78100 (31.3)^(c) 97800 (19.5) AUC_(0-τ(norm)) 11300 (34.1)^(a) 12600(34.9) 10500 (26.9)^(c) 13100 (14.8) (hr*ng/mL/(mg/kg)) C_(max) (ng/mL)6080 (20.7) 6060 (20.1) 8510 (16.2) 9440 (10.8) C_(max (norm)) 1970(30.5) 1970 (28.5) 1140 (11.3) 1260 (11.6) (ng/mL/(mg/kg)) t_(max) ^(b)(hr) 3.00 (2.00-4.00) 4.00 (2.50-4.02) 3.50 (1.50-4.00) 3.53 (2.50-4.02)t_(1/2) (hr) — 4.89 (23.0)^(b) — 6.25 (60.3)^(c) λ_(Z) (hr⁻¹) — 0.142(23.0)^(b) — 0.0544 (107.5) CL/F (mL/min) — 85.9 (27.3) — 89.4 (19.5)CL/F_((norm)) ((mL/min)/kg) — 1.32 (34.9) — 1.27 (14.8) V_(z/)F (L) —36.1 (33.7)^(b) — 98.6 (112.1) V_(z/)F_((norm)) — 0.576 (36.0)^(b) —1.40 (110.6) (L/kg) Ae₀₋₁₂ (mg) 105 (18.0) 142 (15.2) 171 (13.3) 185(27.1) Ae₀₋₂₄ (mg) — — 242 (7.2) 284 (19.4) fe₀₋₁₂ (%) 52.5 (18.0) 71.2(15.2) 32.6 (13.3) 35.3 (27.1) fe₀₋₂₄ (%) — — 46.1 (7.2) 54.0 (19.4)CL_(R) (mL/min) 50.2 (45.4) 61.2 (35.7) 51.7 (31.8) 48.3 (32.2) RA_(AUC)— 1.11 (13.3) — 1.25 (13.7) Dose of Compound I 275 mg BID (B3) (N = 6)Parameter Day 1 Day 7 AUC_(0-τ) (hr*ng/mL) 37700 (12.8)^(d) 56500 (13.4)AUC_(0-τ(norm)) 9560 (22.0)^(d) 14300 (35.9) (hr*ng/mL/(mg/kg)) C_(max)(ng/mL) 6070 (11.6) 7500 (10.9) C_(max (norm)) 1540 (18.2) 1900 (30.5)(ng/mL/(mg/kg)) t_(max) ^(b) (hr) 2.28 (1.50-4.00) 2.75 (2.00-4.00)t_(1/2) (hr) — 5.64 (43.6) λ_(Z) (hr⁻¹) — 0.123 (43.6) CL/F (mL/min) —81.1 (13.4) CL/F_((norm)) — 1.16 (35.9) ((mL/min)/kg) V_(z/)F (L) — 39.6(39.3) V_(z/)F_((norm)) (L/kg) — 0.568 (43.6) Ae₀₋₁₂ (mg) 162 (9.7) 190(13.1) Ae₀₋₂₄ (mg) — — fe₀₋₁₂ (%) 58.9 (9.7) 69.1 (13.1) fe₀₋₂₄ (%) — —CL_(R) (mL/min) 71.6 (17.9) 56.1 (16.2) RA_(AUC) — 1.50 (19.1) Ae₀₋₁₂ =amount of GDC-3280 excreted over 12 hours; Ae₀₋₂₄ = amount of GDC-3280excreted over 24 hours; AUC_(0-τ) = area under the concentration-timecurve (AUC) during the dosing interval (τ or tau); C_(max) = maximumobserved plasma concentration; CL/F = apparent total clearance (GDC-3280only); CL_(R) = renal clearance; CV % = coefficient of variation; fe₀₋₁₂= percentage of drug excreted in the first 12 hours; fe₀₋₂₄ = percent ofGDC-3280 excreted over 24 hours; N = number of subjects; norm = bodyweigh-normalized value; RA_(AUC) = accumulation ratio based onAUC_(0-τ); t_(max) = time to maximum concentration; t_(1/2) = apparentterminal elimination half-life; V_(z/)F = apparent volume ofdistribution during the terminal elimination phase (GDC-3280 only);λ_(Z) = apparent terminal elimination rate constant. ^(a)Median(min-max). ^(b)n = 5. ^(c)n = 3. ^(d)τ = 12 hours. ^(e)τ = 24 hours.

Serum Creatinine (Scr) Observations

In addition to the measurement of various PK parameters in both parts ofthe study, the changes in the subjects' serum creatinine levels werealso evaluated in this study. Tables 6A and 6B summarize the change inlevel and percent change in serum creatinine from averaged screening andpre-dosing values for the subjects in SAD study in each treatment group,as applicable. Tables 7A and 7B summarize the change in level andpercent change in serum creatinine from averaged screening andpre-dosing values for the subjects in MAD study. Increases over theupper limit of normal (ULN) in serum creatinine were observed in bothPart A (SAD) and Part B (MAD) of the study. In Part A of the study,changes were observed in about 21% of the exposures of doses of 200 mgor more. In Part B of the study, changes were observed in about 56% ofthe subjects across all dose levels. 25% percent of the subjects in MADstudy had a mean change from baseline ≥0.3 mg/dL in Scr and 50% of thesubjects in the MAD study had a mean percent change from baseline ≥30%.In Part B of the study, 2 subjects (275 mg BID) experienced clinicallysignificant TEAEs of increased creatinine on day 5. The mean change inserum creatinine from a combined screening and pre-dose baseline in theMAD part of the study is illustrated in FIG. 1. In addition, the meanchange in creatinine level from combined screening and pre-dose level inthe MAD part of the study is illustrated in FIG. 2.

TABLE 6A Change in Serum Creatinine level from baseline in SAD study 400mg 800 mg Change in Ser Placebo 25 mg 75 mg 200 mg Fasted Fasted 1600 mgTotal Change < 0.3 mg/dL 14 6 6 6 10 5 6 53 Change ≥ 0.3 mg/dL 0 0 0 0 21 0 3 Total 14 6 6 6 12 6 6 56

TABLE 6B Percent Change in Serum Creatinine level from baseline in SADstudy 400 mg 800 mg Percent Change in Scr Placebo 25 mg 75 mg 200 mgFasted Fasted 1600 mg Total Change < 30% 14 6 6 6 9 4 6 51 Change ≥ 30%0 0 0 0 3 2 0 5 Total 14 6 6 6 12 6 6 56

TABLE 7A Change in Serum Creatinine level from baseline in MAD studyChange 400 mg 550 mg in Scr (200 mg BID) Placebo 525 mg (275 mg BID)Total Change 5 6 5 2 18 <0.3 mg/dL Change 1 0 1 4 6 ≥0.3 mg/dL Total 6 66 6 24

TABLE 7B Percent Change in Serum Creatinine level from baseline in MADstudy Percent Change 400 mg 550 mg in Scr (200 mg BID) Placebo 525 mg(275 mg BID) Total Change 1 6 3 2 12 <30% Change 5 0 3 4 12 ≥30% Total 66 6 6 24

CONCLUSIONS

Compound I was rapidly absorbed in the fasted state following singleoral doses of Compound I, with median t_(max) values ranging from 1.3 to2.5 hours. The geometric mean t_(1/2) was similar for the 25 and 75 mgCompound I doses with a trend to increase with increase in dose rangingfrom 10.2 hours at the 200 mg dose level to 19.8 hours at the 1600-mgdose level.

Systemic exposure (C_(max) and AUC) increased in a dose-proportionalmanner between 25 and 75 mg, and thereafter, less than proportionalincreases were observed for the 200-mg dose and greater. Between the 800and 1600 mg dose there was no increase in AUC and C_(max), reflectingsaturable absorption. The less than proportional increase in systemicexposure was reflected by a dose-dependent decrease in the percent ofCompound I excreted in urine (76.9% at 25 mg to 9.1% at 1600 mg).

In the low-fat fed state, Compound I was rapidly absorbed with t_(max)values ranging from 1.0 to 4.0 hours. In the high-fat fed state, t_(max)was increased, ranging from 1.5 to 6.0 hours. Administration of CompoundI in a high-fat fed state led to 45.8% to 49.0% increases in AUC_(0-∞)and AUC_(0-t), respectively, and a 68.9% increase in C_(max) from thefasted state. Administration in the low-fat fed state also increasedsystemic exposure with 37.1%, 34.7%, and 64.4% increases in AUC_(0-t),AUC_(0-∞), and C_(max), respectively.

A drug-drug interaction with rabeprazole was observed as pretreatmentand co-administration of 20 mg rabeprazole (QD×3) in the low-fat fedstate led to a 23.5%, 22.8%, and 25.0% decrease in AUC_(0-t), AUC_(0-∞),and C_(max), respectively, compared to Compound I alone.

Following multiple dose administration of Compound I at 200 and 275 mgBID and 525 mg QD, steady-state was attained within 2 days. There wasevidence of minimal accumulation by Day 7 (1.1- to 1.5-fold accumulationfor BID and 1.3-fold for the QD regimen). Higher trough and lower peakconcentrations were observed for BID compared to QD dosing regimens.

In Part B of the study, 2 subjects (275 mg BID) experienced clinicalsignificant TEAEs of increased serum creatinine levels on day 5.

What is claimed is:
 1. A method for providing oral Compound I therapy toa subject:

comprising providing a therapeutically effective amount of Compound I tothe subject; and advising the subject not to take a gastric acidreducing agent concomitantly with Compound I.
 2. The method of claim 1,wherein the gastric acid reducing agent is selected from a proton pumpinhibitor (PPI), a histamine 2 receptor antagonist (H2RA), or anantacid, or combinations thereof.
 3. The method of claim 2, wherein thegastric acid reducing agent is a PPI.
 4. The method of claim 3, whereinthe PPI is rabeprazole.
 5. The method of claim 1, further comprisingadvising the subject not to take the gastric acid reducing agent priorto or subsequent to taking the Compound I.
 6. The method of claim 1,further comprising advising the subject to take the Compound I withfood.
 7. The method of claim 1, wherein the subject has an intra-gastricpH equal to or less than
 4. 8. The method of claim 7, wherein thesubject has an intra-gastric pH less than
 3. 9. The method of claim 1,wherein the subject is in need of a gastric acid reducing agent.
 10. Themethod of claim 1, comprising providing a Compound I to the subject at adosage in a range of 1 mg to 5000 mg per day.
 11. A method for providingoral Compound I therapy to a subject:

comprising administering a therapeutically effective amount of CompoundI to the subject and avoiding concomitant administration of a gastricacid reducing agent.
 12. The method of claim 11, wherein the gastricacid reducing agent is selected from a proton pump inhibitor (PPI), ahistamine 2 receptor antagonist (H2RA), or an antacid, or combinationsthereof.
 13. The method of claim 12, wherein the gastric acid reducingagent is a PPI.
 14. The method of claim 13, wherein the PPI israbeprazole.
 15. The method of claim 11, comprising administering theCompound I with food.
 16. The method of claim 11, wherein the subjecthas an intra-gastric pH equal to or less than
 4. 17. The method of claim16, wherein the subject has an intra-gastric pH less than
 3. 18. Themethod of claim 11, wherein the subject is in need of a gastric acidreducing agent.
 19. The method of claim 11, comprising providing aCompound I to the subject at a dosage in a range of 1 mg to 5000 mg perday.
 20. A method for providing Compound I therapy to a subject in needthereof and in need of a gastric acid reducing agent:

comprising administering Compound I to the subject at a dosage of: (i)200 mg BID; (ii) 525 mg QD; or (iii) 275 mg BID; and avoidingco-administration of a gastric acid reducing agent selected from aproton pump inhibitor (PPI), a histamine 2 receptor antagonist (H2RA),an antacid, or combinations thereof.